Intraguild relationships between sympatric predators exposed to lethal control: predator manipulation experiments.
Terrestrial top-predators are expected to regulate and stabilise food webs through their consumptive and non-consumptive effects on sympatric mesopredators and prey. The lethal control of top-predators has therefore been predicted to inhibit top-predator function, generate the release of mesopredators and indirectly harm native fauna through trophic cascade effects. Understanding the outcomes of lethal control on interactions within terrestrial predator guilds is important for zoologists, conservation biologists and wildlife managers. However, few studies have the capacity to test these predictions experimentally, and no such studies have previously been conducted on the eclectic suite of native and exotic, mammalian and reptilian taxa we simultaneously assess. We conducted a series of landscape-scale, multi-year, manipulative experiments at nine sites spanning five ecosystem types across the Australian continental rangelands to investigate the responses of mesopredators (red foxes, feral cats and goannas) to contemporary poison-baiting programs intended to control top-predators (dingoes) for livestock protection. Short-term behavioural releases of mesopredators were not apparent, and in almost all cases, the three mesopredators we assessed were in similar or greater abundance in unbaited areas relative to baited areas, with mesopredator abundance trends typically either uncorrelated or positively correlated with top-predator abundance trends over time. The exotic mammals and native reptile we assessed responded similarly (poorly) to top-predator population manipulation. This is because poison baits were taken by multiple target and non-target predators and top-predator populations quickly recovered to pre-control levels, thus reducing the overall impact of baiting on top-predators and averting a trophic cascade. These results are in accord with other predator manipulation experiments conducted worldwide, and suggest that Australian populations of native prey fauna at lower trophic levels are unlikely to be negatively affected by contemporary dingo control practices through the release of mesopredators. We conclude that contemporary lethal control practices used on some top-predator populations do not produce the conditions required to generate positive responses from mesopredators. Functional relationships between sympatric terrestrial predators may not be altered by exposure to spatially and temporally sporadic application of non-selective lethal control.


The Potential of the Ni-Resistant TCE-Degrading Pseudomonas putida W619-TCE to Reduce Phytotoxicity and Improve Phytoremediation Efficiency of Poplar Cuttings on A Ni-TCE Co-Contamination.
To examine the potential of Pseudomonas putida W619-TCE to improve phytoremediation of Ni-TCE co-contamination, the effects of inoculation of a Ni-resistant, TCE-degrading root endophyte on Ni-TCE phytotoxicity, Ni uptake and trichloroethylene (TCE) degradation of Ni-TCE-exposed poplar cuttings are evaluated. After inoculation with P. putida W619-TCE, root weight of non-exposed poplar cuttings significantly increased. Further, inoculation induced a mitigation of the Ni-TCE phytotoxicity, which was illustrated by a diminished exposure-induced increase in activity of antioxidative enzymes. Considering phytoremediation efficiency, inoculation with P. putida W619-TCE resulted in a 45% increased Ni uptake in roots as well as a slightly significant reduction in TCE concentration in leaves and TCE evapotranspiration to the atmosphere. These results indicate that endophytes equipped with the appropriate characteristics can assist their host plant to deal with co-contamination of toxic metals and organic contaminants during phytoremediation. Furthermore, as poplar is an excellent plant for biomass production as well as for phytoremediation, the obtained results can be exploited to produce biomass for energy and industrial feedstock applications in a highly productive manner on contaminated land that is not suited for normal agriculture. Exploiting this land for biomass production could contribute to diminish the conflict between food and bioenergy production.


68Ga-Galmydar: A PET imaging tracer for noninvasive detection of Doxorubicin-induced cardiotoxicity.
Cancer patients undergoing Doxorubicin (DOX) treatment are susceptible to acute and chronic cardiac anomalies, including aberrant arrhythmias, ventricular dysfunction, and heart failure. To stratify patients at high risk for DOX -related heart failure (CHF), diagnostic techniques have been sought. While echocardiography is used for monitoring LVEF and LV volumes due to its wide-availability and cost-efficiency, it may not identify early stages of the initiation of DOX-induced systolic heart failure. To address these limitations, PET tracers could also provide noninvasive assessment of early and reversible metabolic changes of the myocardium. Herein, we report a preliminary investigation of 68Ga-Galmydar potential to monitor Dox-induced cardiomyopathy in vivo, ex vivo, and in cellulo employing both nuclear- and optical imaging. To assess 68Ga-Galmydar ability for monitoring DOX-induced cardiomyopathy, microPET imaging was performed 5 d post treatment of rats either with a single dose of DOX (15 mg/kg) or vehicle as a control (saline) and images were co-registered for anatomical reference using CT. Following tail-vein injection of the radiotracer in rats at 60 min, micro-PET/CT static scan (10 min acquisition), 68Ga-Galmydar demonstrated 1.91-fold lower uptake in hearts of DOX-treated (standard uptake value; SUV: 0.92, n = 3) rats compared with their vehicle treated (SUV: 1.76, n = 3) control counterparts. For correlation of PET imaging data, post-imaging quantitative biodistribution studies were also performed, wherein excised organs were counted for γ activity, and normalized to injected dose. The post imaging pharmacokinetic data also demonstrated heart uptake values of 2.0 fold lower for DOX treated rats(%ID/g; DOX: 0.44 ± 0.1, n = 3) compared to their vehicle-treated controls (%ID/g; Control: 0.89 ± 0.03, n = 3, p = 0.04). Employing the fluorescent traits of Galmydar, live cell fluorescence imaging indicated a gradual decrease in uptake and retention of Galmydar within mitochondria of H9c2 cells following DOX-treatment, while indicating dose-dependent and time-dependent uptake profiles. Following depolarization of electronegative transmembrane gradients at the mitochondrial membrane, the uptake of the probe was decreased in H9c2 cells, and the uptake profiles were found to be identical, using both fluorescence and radiotracer bioassays. Finally, the decreased uptake of the metalloprobe in H9c2 cells also correlated with caspase-3 expression resulting from DOX-induced cardiotoxicity and cell death. 68Ga-Galmydar could provide a noninvasive assessment of DOX-related and likely reversible metabolic changes at earliest stages. Further studies with other chemotherapeutics (potentially capable of inducing cardiomyopathy) are underway.


Clinical assessment of osteoarthritis of the knee.
The repeatability of physical signs used to assess osteoarthritis of the knee has not been systematically examined. The within and between observer variation of 10 commonly used physical signs to determine osteoarthritis of the knee has been assessed here. The results obtained show variation in the repeatability of these signs. For those examining the tibiofemoral joints the repeatability was greater than for those examining the patellofemoral joint. It would therefore seem vital to take note of the repeatability of physical signs in determining the number of subjects to be studied in epidemiological studies and therapeutic studies in osteoarthritis.


Cystic tumors of the pancreas: a radiological perspective.
The purpose of this article is to highlight the imaging features of cystic pancreatic tumors. Common cystic pancreatic tumors include serous microcystic adenomas, mucinous cystic tumors, intraductal papillary mucinous neoplasms and solid pseudopapillary tumors. These tumors have characteristic imaging features, especially on magnetic resonance imaging (MRI) and MR cholangiopancreaticography examinations. Imaging findings allow a reasonable differential diagnosis between benign and malignant cystic pancreatic tumors. Thus, accurate imaging characterization of these lesions may lead to accurate patient care and prevent unnecessary surgical interventions.


Predicting kindergarten peer social status from toddler and preschool problem behavior.
The aim of this study was to investigate the toddler and preschool predictors of early peer social preference. Behavioral and social functioning were examined in a sample of children across the toddler and preschool years from parent and teacher observations. Kindergarten social behavior and peer social preference were assessed in the children's kindergarten classrooms using standard sociometric techniques. Results indicated that parent report of toddler externalizing behavior and teacher report of preschool problem behavior, as indexed by aggressive behavior, social skills, and emotional regulation, were predictive of peer liking in kindergarten. However, this relation was mediated by specific behaviors evidenced in the kindergarten classroom. For boys, overt aggression mediated these relations. For girls, sharing and engaging in sneaky behavior in kindergarten mediated the relation between preschool problem behaviors and peer status. These results indicate that specific behaviors displayed in the peer group account for the relation between early problem behavior and peer status. Moreover, these data point to the importance of considering gender when examining developmental trajectories and outcomes.


The endoscopy Global Rating Scale-Canada: development and implementation of a quality improvement tool.
Increasing use of gastrointestinal endoscopy, particularly for colorectal cancer screening, and increasing emphasis on health care quality highlight the need for endoscopy facilities to review the quality of the service they offer. To adapt the United Kingdom Global Rating Scale (UK-GRS) to develop a web-based and patient-centred tool to assess and improve the quality of endoscopy services provided. Based on feedback from 22 sites across Canada that completed the UK endoscopy GRS, and integrating results of the Canadian consensus on safety and quality indicators in endoscopy and other Canadian consensus reports, a working group of endoscopists experienced with the GRS developed the GRS-Canada (GRS-C). The GRS-C mirrors the two dimensions (clinical quality and quality of the patient experience) and 12 patient-centred items of the UK-GRS, but was modified to apply to Canadian health care infrastructure, language and current practice. Each item is assessed by a yes⁄no response to eight to 12 statements that are divided into levels graded D (basic) through A (advanced). A core team consisting of a booking clerk, charge nurse and the physician responsible for the unit is recommended to complete the GRS-C twice yearly. The GRS-C is intended to improve endoscopic services in Canada by providing endoscopy units with a straightforward process to review the quality of the service they provide.


Variation by body mass index and age in waist-to-hip ratio associations with glycemic status in an aboriginal population at risk for type 2 diabetes in British Columbia, Canada.
It is unclear whether obesity and age modify or confound relations between abdominal adiposity and metabolic risk factors for type 2 diabetes. Our objective was assess the consistency of relations between abdominal adiposity and glycemic variables across discrete categories of obesity and age. We performed a stratified analysis of prevalence data from a rural screening initiative in British Columbia, Canada. Subjects were Salishan Indians, all healthy relatives of individuals with type 2 diabetes [n = 151; age: 18-80 y; body mass index (BMI, in kg/m2): 17.0-48.2]. We measured waist-to-hip ratio (WHR) (2 categories); insulin, glycated hemoglobin (Hb A1c), and 2-h glucose concentrations (2 categories); and BMI (4 categories). BMI and age-specific odds ratios (ORs) and 95% CIs were calculated. WHR-glycemic variable relations were not consistent across BMI and age strata. Risks associated with high WHR were: for persons with BMIs from 25 to 29, elevated insulin (OR: 6.71; 95% CI: 1.41, 34.11) and Hb A1c (OR: 16.23; 95% CI: 2.04, 101.73) concentrations; for persons aged 18-34 y, elevated insulin concentrations [OR: indeterminate (+infinity); 95% CI: 1.89, +infinity]; and, for persons aged 35-49 y, elevated Hb A1c (OR: +infinity; 95% CI: 3.17, +infinity) and 2-h glucose (OR: 9.15; 95% CI: 1.74, 59.91) concentrations. WHR discriminates risk of type 2 diabetes in overweight but not obese individuals. Abdominal adiposity is associated with elevated insulin concentrations in younger age groups and with impaired glucose control in middle-aged groups, suggesting metabolic staging by age on a continuum from insulin resistance to impaired glucose tolerance.


Occurrence of Mycosis Fungoides in an Iranian Chemical Victim of the Iran-Iraq War with a Long-term Follow-Up: A Case Report and Review of Literature.
Mycosis fungoides (MF) is the most common form of cutaneous T-cell lymphoma. Persistent antigenic stimulation has been claimed to play a role in the development of this malignancy. We aimed to show the role of sulfur mustard in the pathogenesis of MF. A 45-year-old man with MF is introduced herein. He was a victim of chemical exposure in 1987 during the Iran-Iraq war. He developed skin lesions 3 years after exposure to sulfur mustard gas at the age of 21. Seven years after his exposure to sulfur mustard gas, a biopsy from the posterior distal part of his calf, which was injured and had bulla, revealed MF. Later, he developed more lesions on his extremities, trunk, and abdomen. On his previous admission, his left eyebrow was involved. A punch biopsy specimen was obtained from his eyebrow lesion, which rendered diffuse infiltration of atypical lymphocyte cells with some convoluted nuclei and scant cytoplasm admixed with lymphocytes, histiocytes, and mast cells compatible with the nodular stage of MF. At his last admission, a biopsy was obtained from the plaque lesions on his left thigh, and a TCR-γ gene rearrangement of the paraffin block of the plaque lesions revealed positive monoclonality. All the findings supported the MF diagnosis. We concluded that sulfur mustard could be a risk factor for MF development.


Effects of ethanol on the permeability of frog skin.
Ethanol (3%) decreases the potential difference and short-circuit current across the isolated frog skin in chloride Ringer's solution. Unidirectional fluxes of Na and Cl indicate that the drop in short-circuit current is due to an inhibition of the sodium influx. However, ethanol had no effect on the electrical parameters or sodium fluxes, when the frog skin was bathed in chloride-free solutions on both sides or the outside alone. The ethanol response is anion-dependent. In addition, chloride-free media in the inside bathing solution reduced the short-circuit current, indicating a sodium transport pathway which is dependent on chloride and confirming previous data in the literature. Other anions such as sulfate and nitrate could not substitute for chloride. The vasopressin-induced natriferic response and the ethanol effect were found to work independently of each other and different pathways of action are suggested for these agents. The intracellular sodium content of the isolated frog skin epithelium increased and potassium decreased in the presence of the Na-K adenosine triphosphatase inhibitor, ouabain, whereas ethanol or amiloride had no effect. The oxygen consumption of the isolated frog skin was unaffected by up to 10% ethanol. A general metabolic action is probably thus not mediating the response. Urea, in iso-osmotic concentrations to the ethanol, did not mimic its effect. Tritiated water fluxes (in the absence of an osmotic gradient) were reduced by 30% in the presence of 3% ethanol. It is suggested that ethanol may impede the flow of water across frog skin by a physicochemical interaction with membrane pores and the water molecules. The permeability coefficient (Ktrans) for ethanol was found to be 10 times smaller than the Ktrans for water.


Prevalence and characterization of methicillin-resistant Staphylococcus aureus isolates from healthy university student athletes.
The prevalence of methicillin-resistant Staphylococcus aureus (MRSA) has been increasing in the general population, and there is concern that close or physical contact, such as in professional and collegiate sports, may increase spread of MRSA. We sought to determine the prevalence of MRSA colonization of male and female athletes from 9 different sports at a major, Division I University during a 12-week period, and determine the USA and SCCmec type from select isolates. Swabs for culture of MRSA were obtained from nasal, axillary, and inguinal sites from healthy, asymptomatic student athletes and support staff each week for 12 weeks. Select MRSA isolates were typed by pulsed field gel electrophoresis (PFGE), and the genes encoding for MecA, cassette chromosome recombinase (Ccr), and several toxins were determined by multiplex polymerase chain reaction (PCR). Discrepant results were clarified by multi-locus sequence typing (MLST) and spa typing. Thirty-five percent (78/223) of test subjects were positive for MRSA during the study period, resulting in isolation of 139 MRSA isolates. However, 47% (37/78) of MRSA-positive participants carried MRSA in axillary or inguinal sites, but not in the anterior nares. There was significant correlation between MRSA carriage and participation in wrestling (76%, 19/25; adjusted odds ratio 29.7, 95% CI 5.8-151.5) and baseball (44%, 17/39; adjusted odds ratio 4.4, 95% CI 1.1- 17.4), compared with a staff prevalence of 18.1% (4/22), but other factors were not examined. Multiplex PCR analysis indicated that of the 32 isolates examined 26 could be typed, and all of these carried the SCCmec type IV cassette. PFGE typing identified USA types 300, 400, 500, 700, and 800. However, one isolate was not a known USA type, but was identified as a novel ST951 by MLST, and as spa type t216. Of the strains typed from the same individual, there was consistency, but also variation and alternation of the SCCmec and spa types isolated from individual subjects. Various staphylococcal toxin genes were identified in 31 of the 32 isolates analyzed. Colonization by MRSA was greater in some student athletes than the average carriage rate for the general population, and only 53% of MRSA carriers were identified by nasal cultures. Carriage of MRSA clones on the same individual and transmission to contacts could vary over time, indicating colonization can be a dynamic process that may be difficult to control.


Reaction rate of a composite core-shell nanoreactor with multiple nanocatalysts.
We present a detailed theory for the total reaction rate constant of a composite core-shell nanoreactor, consisting of a central solid core surrounded by a hydrogel layer of variable thickness, where a given number of small catalytic nanoparticles are embedded at prescribed positions and are endowed with a prescribed surface reaction rate constant. Besides the precise geometry of the assembly, our theory accounts explicitly for the diffusion coefficients of the reactants in the hydrogel and in the bulk as well as for their transfer free energy jump upon entering the hydrogel shell. Moreover, we work out an approximate analytical formula for the overall rate constant, which is valid in the physically relevant range of geometrical and chemical parameters. We discuss in depth how the diffusion-controlled part of the rate depends on the essential variables, including the size of the central core. In particular, we derive some simple rules for estimating the number of nanocatalysts per nanoreactor for an efficient catalytic performance in the case of small to intermediate core sizes. Our theoretical treatment promises to provide a very useful and flexible tool for the design of superior performing nanoreactor geometries with optimized nanoparticle load.


General anesthesia and contrast-enhanced computed tomography to optimize renal percutaneous radiofrequency ablation: multi-institutional intermediate-term results.
Percutaneous renal ablation is often performed under conscious sedation and without contrast-enhanced imaging. We evaluated intermediate-term outcomes of patients undergoing percutaneous contrast-enhanced computed tomography (CT)-guided radiofrequency ablation (RFA) under general anesthesia (GA) at two high-volume centers. Prospectively maintained Institutional Regulatory Board-approved databases were searched to identify patients treated with percutaneous RFA using contrast-enhanced CT under GA. A total of 163 masses in 151 patients were treated. Enhancement on imaging or a positive biopsy at 4 to 6 weeks was considered incomplete ablation. Positive findings beyond this interval were defined as local recurrence. The median follow-up was 18 months (range, 1.5-70). Median tumor size was 2.3 cm (range, 1-5.4). Of the 130 (80%) masses with definitive pathology, 70% were renal cell cancer. Five masses had evidence of viable tumor at 4 to 6 weeks posttreatment for a complete initial ablation rate of 97%. Three of these five lesions were endophytic. Five masses (3.3%) showed evidence of local recurrence, and metastases developed in two patients (1.3%). Overall 1- and 3-year recurrence-free survival was 97% and 92%, respectively. Masses that were in the central region and were endophytic had the highest risk for recurrence (hazard ratio, 6.3; p = 0.016). Intermediate-term outcomes of percutaneous RFA are excellent. GA-assisted, contrast-enhanced CT-guided percutaneous RFA demonstrates a high initial ablation success rate. However, endophytic and interpolar lesions are at higher risk for recurrence.


Milk progesterone profiles in crossbred Brown Swiss x Nellore cattle following natural service.
Ovarian activity and estrous behaviour were monitored through milk progesterone determinations and twice daily visual observations in 70 crossbred Brown Swiss x Nellore cows following natural service. Whole milk samples were collected on the day of estrus (Day 1), Day 11, and every 5 d thereafter until the next estrus or pregnancy confirmation. Seventy percent of the cows behaved as expected, i.e. they showed a 19-to 25-d interval between estrus and the next ovulation, or they became pregnant. Estrous cycles of regular length (18 to 24 d) were found in 54% of the cases. Prolonged luteal phases (interval from estrus to next ovulation > 28 d) were found in 15.7% of cows. Short estrous cycles (interestrous interval < 18 d) were found in 7.1% of the cases. Periods of acyclicity (basal progesterone levels for periods >/= 15 d) were found in 5.8% of the cases, and one cow exhibited estrus while pregnant and had a high progesterone concentration. Cows with a prolonged luteal phase and those with a short estrous cycle had an interval between ovulations of 35.0 +/- 6.7 d (x +/- SD) and 9.6 +/- 3.1 d, respectively. Signs of estrus were not detected in 33.3% of the ovulations confirmed by progesterone determinations. Low conception rates, failures in estrus detection and a high frequency of abnormal postbreeding luteal phases were found.


Origin of metastable oligomers and their effects on amyloid fibril self-assembly.
Assembly of rigid amyloid fibrils with their characteristic cross-β sheet structure is a molecular signature of numerous neurodegenerative and non-neuropathic disorders. Frequently large populations of small globular amyloid oligomers (gOs) and curvilinear fibrils (CFs) precede the formation of late-stage rigid fibrils (RFs), and have been implicated in amyloid toxicity. Yet our understanding of the origin of these metastable oligomers, their role as on-pathway precursors or off-pathway competitors, and their effects on the self-assembly of amyloid fibrils remains incomplete. Using two unrelated amyloid proteins, amyloid-β and lysozyme, we find that gO/CF formation, analogous to micelle formation by surfactants, is delineated by a "critical oligomer concentration" (COC). Below this COC, fibril assembly replicates the sigmoidal kinetics of nucleated polymerization. Upon crossing the COC, assembly kinetics becomes biphasic with gO/CF formation responsible for the lag-free initial phase, followed by a second upswing dominated by RF nucleation and growth. RF lag periods below the COC, as expected, decrease as a power law in monomer concentration. Surprisingly, the build-up of gO/CFs above the COC causes a progressive increase in RF lag periods. Our results suggest that metastable gO/CFs are off-pathway from RF formation, confined by a condition-dependent COC that is distinct from RF solubility, underlie a transition from sigmoidal to biphasic assembly kinetics and, most importantly, not only compete with RFs for the shared monomeric growth substrate but actively inhibit their nucleation and growth.


Carcinoma of the lung in HIV-positive patients: findings on chest radiographs and CT scans.
Several recent clinical studies have described an association between HIV seropositivity and lung cancer. The purpose of this study was to describe the spectrum of imaging findings in HIV-positive patients who had proved carcinoma of the lung. In particular, we attempted to define the role of CT in diagnosing HIV-associated lung cancer. The study population consisted of 23 HIV-positive patients from two institutions who had lung cancer diagnosed between 1989 and 1993. All patients had both chest radiographs and CT scans. The group included 19 men and four women with a mean age of 42 years. The diagnosis of lung cancer was confirmed by bronchoscopy in eight patients, by pleural fluid aspiration or pleural biopsy in seven, by percutaneous needle biopsy of a lung lesion in three, by biopsy of an extrathoracic site in four, and by thoracotomy in one. Two thoracic radiologists retrospectively evaluated the chest radiographs and CT scans to identify parenchymal masses, lymphadenopathy, pleural disease, chest wall or mediastinal invasion, and metastatic lesions. Fifteen (65%) of the 23 patients had a central or peripheral mass or nodule. Eight (35%) had extensive pleural disease, either as an isolated finding or in combination with other abnormalities. CT scans showed the malignant lesion underlying the extensive pleural disease in all but one case. All patients with extensive pleural disease had adenocarcinoma. No patient in the study was considered a candidate for resection on the basis of clinical and radiologic evaluation. Lung cancer in HIV-positive patients manifested most often on chest radiographs as a central or peripheral mass or nodule. Extensive pleural disease in the absence of an apparent primary lesion was the second most common major manifestation. Lung cancer therefore merits serious consideration in the differential diagnosis of extensive pleural disease in HIV-positive patients. CT was most useful in evaluating malignant lesions associated with extensive pleural disease.


Multiple central place foraging by spider monkeys: travel consequences of using many sleeping sites.
Central place foraging models assume that animals return to a single central place such as a nest, burrow, or sleeping site. Many animals, however choose between one of a limited number of central places. Such animals can be considered Multiple Central Place Foragers (MCPF), and such a strategy could reduce overall travel costs, if the forager selected a sleeping site close to current feeding areas. We examined the selection of sleeping sites (central places) by a community of spider monkeys (Ateles geoffroyi) in Santa Rosa National Park, Costa Rica in relation to the location of their feeding areas. Spider monkeys repeatedly used 11 sleeping trees, and they tended to choose the sleeping site closest to their current feeding area. A comparison of the observed travel distances with distances predicted for a MCPF strategy, a single central place strategy, and a strategy of randomly selecting sleeping sites demonstrated (1) that the MCPF strategy entailed the lowest travel costs, and (2) that the observed travel distance was best predicted by the MCPF strategy. Deviations between the observed distance travelled and the values predicted by the MCPF model increased after a feeding site had been used for several days. This appears to result from animals sampling their home range to locate new feeding sites.


Exploiting the potential of intranet for managing drug spectrum a web base publication in a Tertiary Care Hospital in Mumbai.
The study surveyed the availability of the intranet in campus and also the knowledge related to drug spectrum an intranet publication. Institutional ethics committee permission was obtained. Verbal consent was taken from the faculty and resident doctors of departments where all the facilities were available. Universal sampling method was used for recruitment. Pre-validated questionnaires were given to approximately 100 faculty and 500 resident doctors in the year 2012-2013. The questionnaire contained 15 items. Content analysis was done. The study questionnaire focused on a survey to obtain participants feedback on the use of the intranet and to evaluate the use of intranet as a source of knowledge. It also dealt on the relevance of the drug spectrum in the context of their subject. The responses were taken after giving the participants sufficient time. Data was entered into an Excel 2003 spread sheet and analyzed by using descriptive statistics. The total number of respondents who participated in our study was 134 including faculty and residents from various departments. A total of 117 (89.66%) respondents stated that their departments have access to the internet. Departments having access to intranet was 103 (76.29%). 67 (49.62%) respondents have accessed. 67 (49.62%) did not have the time to visit intranet site whereas 67 (49.62%) have not accessed intranet. 89 (65.92%) respondents were not aware of the drug spectrum. 101 (74.81%) respondents felt that drug spectrum is a useful activity on intranet. 45 (33.33%) knew about the intranet periodical drug spectrum, but most of the respondents (33.33%) explained the meaning of the word drug spectrum according to their understanding, but never knew about the online intranet journal drug spectrum. The study found that the intranet is available in the campus, but it is not being utilized. The awareness and knowledge regarding drug spectrum is lacking, but the participants had a lot of suggestions. Thus, intranet has immense utility, and to make drug spectrum more readable suggestions of the respondents needs to be incorporated which in turn can benefit the medical fraternity as a whole.


Associations between infectious mononucleosis and cancer: record-linkage studies.
Infection with Epstein-Barr virus (EBV) followed by infectious mononucleosis (IM) is now considered to be a risk factor for Hodgkin's disease (HD). It is less clear whether EBV infection and IM are associated with an increased risk of cancer generally. We used a longstanding record-linkage dataset in Oxford (years 1963-1998), and a more recent record-linkage dataset covering England (1999-2005), to compare rate ratios for cancer between people admitted to hospital for IM and a reference cohort. In the Oxford cohort, there was an increased risk of subsequent HD [rate ratio (RR) 6.0, 95% confidence interval (CI) 2.4-12.5] but not of other cancers combined (RR 0.85, 95% CI 0.57-1.23). In the England cohort, there were increased risks of HD (RR 3.2, 95% CI 1.2-7.0), non-Hodgkin's lymphoma (RR 5.6, 95% CI 2.9-9.8), and oropharyngeal cancer (RR 5.4, 95% CI 1.1-16.2), but no significant overall risk of cancer when lymphomas were excluded (RR 1.01, 95% CI 0.71-1.41). We confirm an association between IM and lymphoma; but the risk, if any, of cancer more generally is likely to be small.


Changes in malaria parasite drug resistance in an endemic population over a 25-year period with resulting genomic evidence of selection.
Analysis of genome-wide polymorphism in many organisms has potential to identify genes under recent selection. However, data on historical allele frequency changes are rarely available for direct confirmation. We genotyped single nucleotide polymorphisms (SNPs) in 4 Plasmodium falciparum drug resistance genes in 668 archived parasite-positive blood samples of a Gambian population between 1984 and 2008. This covered a period before antimalarial resistance was detected locally, through subsequent failure of multiple drugs until introduction of artemisinin combination therapy. We separately performed genome-wide sequence analysis of 52 clinical isolates from 2008 to prospect for loci under recent directional selection. Resistance alleles increased from very low frequencies, peaking in 2000 for chloroquine resistance-associated crt and mdr1 genes and at the end of the survey period for dhfr and dhps genes respectively associated with pyrimethamine and sulfadoxine resistance. Temporal changes fit a model incorporating likely selection coefficients over the period. Three of the drug resistance loci were in the top 4 regions under strong selection implicated by the genome-wide analysis. Genome-wide polymorphism analysis of an endemic population sample robustly identifies loci with detailed documentation of recent selection, demonstrating power to prospectively detect emerging drug resistance genes.


Controlling crystal phases in GaAs nanowires grown by Au-assisted molecular beam epitaxy.
Control of the crystal phases of GaAs nanowires (NWs) is essential to eliminate the formation of stacking faults which deteriorate the optical and electronic properties of the NWs. In addition, the ability to control the crystal phase of NWs provides an opportunity to engineer the band gap without changing the crystal material. We show that the crystal phase of GaAs NWs grown on GaAs(111)B substrates by molecular beam epitaxy using the Au-assisted vapor-liquid-solid growth mechanism can be tuned between wurtzite (WZ) and zinc blende (ZB) by changing the V/III flux ratio. As an example we demonstrate the realization of WZ GaAs NWs with a ZB GaAs insert that has been grown without changing the substrate temperature.


Prehospital randomised assessment of a mechanical compression device in cardiac arrest (PaRAMeDIC) trial protocol.
Survival after out-of-hospital cardiac arrest is closely linked to the quality of CPR, but in real life, resuscitation during prehospital care and ambulance transport is often suboptimal. Mechanical chest compression devices deliver consistent chest compressions, are not prone to fatigue and could potentially overcome some of the limitations of manual chest compression. However, there is no high-quality evidence that they improve clinical outcomes, or that they are cost effective. The Prehospital Randomised Assessment of a Mechanical Compression Device In Cardiac Arrest (PARAMEDIC) trial is a pragmatic cluster randomised study of the LUCAS-2 device in adult patients with non-traumatic out-of-hospital cardiac arrest. The primary objective of this trial is to evaluate the effect of chest compression using LUCAS-2 on mortality at 30 days post out-of-hospital cardiac arrest, compared with manual chest compression. Secondary objectives of the study are to evaluate the effects of LUCAS-2 on survival to 12 months, cognitive and quality of life outcomes and cost-effectiveness. Ambulance service vehicles will be randomised to either manual compression (control) or LUCAS arms. Adult patients in out-of-hospital cardiac arrest, attended by a trial vehicle will be eligible for inclusion. Patients with traumatic cardiac arrest or who are pregnant will be excluded. The trial will recruit approximately 4000 patients from England, Wales and Scotland. A waiver of initial consent has been approved by the Research Ethics Committees. Consent will be sought from survivors for participation in the follow-up phase. The trial will assess the clinical and cost effectiveness of the LUCAS-2 mechanical chest compression device. The trial is registered on the International Standard Randomised Controlled Trial Number Registry (ISRCTN08233942).


Role of Lopinavir/Ritonavir in the Treatment of Covid-19: A Review of Current Evidence, Guideline Recommendations, and Perspectives.
A life-threatening respiratory illness (COVID-19) due to severe acute respiratory syndrome (SARS)-CoV-2 coronavirus was first described in December 2019 in Wuhan (China), rapidly evolving into a pandemic. In the first phase, when the viral replication plays a pivotal pathogenetic role, antiviral drugs could be crucial in limiting viral-induced organ damage. Unfortunately, there are no specific antivirals of proven efficacy for COVID-19, and several drugs have been repurposed to face this dramatic pandemic. In this paper we review the studies evaluating lopinavir/ritonavir association (LPV/r) use in COVID-19, and previously in SARS and Middle East respiratory syndrome (MERS). We searched PubMed to identify all relevant clinical and laboratory studies published up to 15 May 2020; the guidelines on the use of LPV/r in COVID-19 were further directly searched on the website of the main international scientific societies and agencies. Available evidence is currently scarce and of low quality. The recommendations issued for COVID-19 vary from positions clearly against the use of LPV/r to other positions that are more favorable. In our opinion, despite the controversial results of an important randomized clinical trial, and some recommendations, clinicians should not abandon the use of LPV/r for the treatment of COVID-19, possibly using this drug inside a prospective randomized trial, waiting for the results of the numerous ongoing trials evaluating its efficacy.


A sex difference in the predisposition for physical competition: males play sports much more than females even in the contemporary U.S.
Much evidence indicates that men experienced an evolutionary history of physical competition, both one-on-one and in coalitions. We thus hypothesized that, compared to girls and women, boys and men will possess a greater motivational predisposition to be interested in sports, especially team sports. According to most scholars, advocacy groups, and the United States courts, however, this hypothesis is challenged by modest sex differences in organized school sports participation in the contemporary U.S., where females comprise 42% of high school participants and 43% of intercollegiate participants. We conducted three studies to test whether organized school sports participation data underestimate the actual sex difference in sports participation. Study 1 analyzed the American Time Use Survey, which interviewed 112,000 individuals regarding their activities during one day. Females accounted for 51% of exercise (i.e., non-competitive) participations, 24% of total sports participations, and 20% of team sports participations. These sex differences were similar for older and younger age groups. Study 2 was based on systematic observations of sports and exercise at 41 public parks in four states. Females accounted for 37% of exercise participations, 19% of individual sports participations, and 10% of team sports participations. Study 3 involved surveying colleges and universities about intramural sports, which primarily consist of undergraduate participation in team sports. Across 34 institutions, females accounted for 26% of registrations. Nine institutions provided historical data, and these did not indicate that the sex difference is diminishing. Therefore, although efforts to ensure more equitable access to sports in the U.S. (i.e., Title IX) have produced many benefits, patterns of sports participation do not challenge the hypothesis of a large sex difference in interest and participation in physical competition.


Evaluation of Disaster Preparedness Based on Simulation Exercises: A Comparison of Two Models.
The objective of this study was to highlight 2 models, the Hospital Incident Command System (HICS) and the Disaster Management Indicator model (DiMI), for evaluating the in-hospital management of a disaster situation through simulation exercises. Two disaster exercises, A and B, with similar scenarios were performed. Both exercises were evaluated with regard to actions, processes, and structures. After the exercises, the results were calculated and compared. In exercise A the HICS model indicated that 32% of the required positions for the immediate phase were taken under consideration with an average performance of 70%. For exercise B, the corresponding scores were 42% and 68%, respectively. According to the DiMI model, the results for exercise A were a score of 68% for management processes and 63% for management structure (staff skills). In B the results were 77% and 86%, respectively. Both models demonstrated acceptable results in relation to previous studies. More research in this area is needed to validate which of these methods best evaluates disaster preparedness based on simulation exercises or whether the methods are complementary and should therefore be used together. (Disaster Med Public Health Preparedness. 2016;10:544-548).


Methylene blue for malaria in Africa: results from a dose-finding study in combination with chloroquine.
The development of safe, effective and affordable drug combinations against malaria in Africa is a public health priority. Methylene blue (MB) has a similar mode of action as chloroquine (CQ) and has moreover been shown to selectively inhibit the Plasmodium falciparum glutathione reductase. In 2004, an uncontrolled dose-finding study on the combination MB-CQ was performed in 435 young children with uncomplicated falciparum malaria in Burkina Faso (CQ monotherapy had a > 50% clinical failure rate in this area in 2003). Three serious adverse events (SAE) occurred of which one was probably attributable to the study medication. In the per protocol safety analysis, there were no dose specific effects. The overall clinical and parasitological failure rates by day 14 were 10% [95% CI (7.5%, 14.0%)] and 24% [95% CI (19.4%, 28.3%)], respectively. MB appears to have efficacy against malaria, but the combination of CQ-MB is clearly not effective in the treatment of malaria in Africa.


Evidence-based dietary management of functional gastrointestinal symptoms: The FODMAP approach.
Functional gastrointestinal symptoms are common and their management is often a difficult clinical problem. The link between food intake and symptom induction is recognized. This review aims to describe the evidence base for restricting rapidly fermentable, short-chain carbohydrates (FODMAPs) in controlling such symptoms. The nature of FODMAPs, their mode of action in symptom induction, results of clinical trials and the implementation of the diet are described. FODMAPs are widespread in the diet and comprise a monosaccharide (fructose), a disaccharide (lactose), oligosaccharides (fructans and galactans), and polyols. Their ingestion increases delivery of readily fermentable substrate and water to the distal small intestine and proximal colon, which are likely to induce luminal distension and induction of functional gut symptoms. The restriction of their intake globally (as opposed to individually) reduces functional gut symptoms, an effect that is durable and can be reversed by their reintroduction into the diet (as shown by a randomized placebo-controlled trial). The diet has a high compliance rate. However it requires expert delivery by a dietitian trained in the diet. Breath hydrogen tests are useful to identify individuals who can completely absorb a load of fructose and lactose so that dietary restriction can be less stringent. The low FODMAP diet provides an effective approach to the management of patients with functional gut symptoms. The evidence base is now sufficiently strong to recommend its widespread application.


Predictive therapeutic planning for irreversible electroporation treatment of spontaneous malignant glioma.
Irreversible electroporation (IRE) has been developed as a promising minimally invasive treatment to ablate spontaneous brain tumors with pulsed electric fields in canine patients. The purpose of the study is to determine the Peleg-Fermi parameters needed to incorporate pulse number and pulse duration into the therapeutic planning of IRE. Seven canine patients were treated with IRE for spontaneous malignant glioma with MRI-based treatment planning. The treatment planning method consists of building patient-specific finite element models and using them to compute electric fields used in the IRE treatment. We evaluate the predictive power of tumor coverage with electric field alone vs. cell kill probability using radiographically confirmed clinical outcomes. Results of post-treatment diagnostic imaging, tumor biopsies, and neurological examinations indicated successful tumor ablation without significant direct neurotoxicity in six of the seven dogs. Objective tumor responses were seen in four (80%) of five dogs with quantifiable target lesions according to RANO criteria. Two dogs experienced survivals in excess of 1 yr, including one dog that resulted in complete response to IRE treatment for 5+ years to date. Tumor fraction exposed to electric field over 600 V/cm was between 0.08 and 0.73, while tumor fraction exposed to electric field over 300 V/cm was between 0.17 and 0.95. Probability of cell kill of ≥ 90% was found in tumor volume fractions between 0.21 and 0.99. We conclude that IRE is a safe and effective minimally invasive treatment for malignant glioma and can be predicted with the Peleg-Fermi cell kill probability function. A tumor coverage of ≥ 0.9 at a cell kill probability ≥ 90% can be used to guide IRE treatments of spontaneous malignant glioma based on the radiographically confirmed clinical outcomes achieved.


Erythropoietin and iron-restricted erythropoiesis.
Twenty five years ago, Finch summarized knowledge gained primarily from studies of normal individuals, patients with hereditary hemolytic anemias, and patients with hemochromatosis [1]. Under conditions of basal erythropoiesis in normal subjects, plasma iron turnover (as an index of marrow erythropoietic response) is little affected, whether transferrin saturation ranges from very low to very high levels. In contrast, the erythropoietic response in individuals with congenital hemolytic anemia, in whom erythropoiesis is chronically raised up to sixfold over basal levels [2], is affected (and limited) by serum iron levels and by transferrin saturation [3]. Patients with hemochromatosis who underwent serial phlebotomy were observed to mount erythropoietic responses of up to eightfold over basal rates, attributed to the maintenance of very high serum iron and transferrin saturation levels in these patients [4], whereas normal individuals were shown to have difficulty providing sufficient iron to support rates of erythropoiesis greater than three times basal rates [5]. These observations led Finch to identify a "relative iron deficiency" state, also known as "functional iron deficiency," which he defined as circumstances in which increased erythron iron requirements exceed the available supply of iron [6]. In another clinical setting, patients undergoing autologous blood donation represent a model for perisurgical blood loss and the erythropoietic response. Insights gained over the last 20 years regarding the relationship between erythropoietin, iron, and erythropoiesis, along with implications for clinical management, will be reviewed.


Comparison of the effects of a 50% exchange-transfusion with albumin, hetastarch, and modified hemoglobin solutions.
We compared the hemodynamic effects of replacing 50% of the blood volume of anesthetized rats with an equal volume of five solutions: human serum albumin (HSA), hetastarch, unmodified hemoglobin, diaspirin-crosslinked hemoglobin, and o-raffinose-crosslinked hemgolobin. Control rats were exchange-transfused with their own blood. HSA and hetastarch caused a severe reduction in systemic vascular resistance (SVR), hypotension, and acute renal failure immediately after the exchange-transfusion. Unmodified and diaspirin-crosslinked hemoglobins caused comparable and severe increases in SVR, whereas vasoconstriction induced by o-raffinose-crosslinked hemoglobin was minimal. The increased SVR induced by all hemoglobin solutions resolved over a 2-day period as the hemoglobin was cleared from plasma. Body weight was monitored for 5 days after the exchange transfusion as a measure of the relative long-term efficacy of the exchange solutions tested and increased substantially in control rats (that received blood). Rats that received both crosslinked hemoglobin solutions gained a comparable amount of weight as the control group. By contrast rats that received HSA, hetastarch and unmodified hemoglobin failed to gain weight or lost weight over the same period. In summary: i) HSA and hetastarch are relatively ineffective as resuscitative fluids when administered after the loss of a large volume of blood; ii) diaspirin-crosslinked hemoglobin causes severe vasoconstriction, comparable in intensity to that induced by unmodified hemoglobin; iii) o-raffinose-crosslinked hemoglobin induces minimal vasoconstriction; iv) the vasoactive effects of all hemoglobin solutions are reversible. We conclude, that of all solutions tested, both the short- and long-term effects of an exchange-transfusion with whole blood are most closely reproduced by an exchange with o-raffinose-crosslinked hemoglobin.


The influence of immunizing dose size and schedule on immunity to subsequent challenge with antigenically distinct strains of Eimeria maxima.
Eimeria maxima, the most immunogenic of the Eimeriidae that infect the chicken, is characterized by the presence of antigenic diversity within field isolates. In priming/challenge experiments immunity to homologous infection is essentially complete while immunity against challenge by a heterologous strain is often only partial. The phenotype "escape from immune protection" is known to be influenced by both host and parasite genotypes but the impact of varied immunization dose and schedule remains poorly documented. In this manuscript we report that an immunizing dose between <or=5 and <or=20 sporulated E. maxima oocysts is consistently capable of stimulating complete (>99.99%) protective immunity against challenge by 100 oocysts of a homologous strain. In contrast, complete immunity against a heterologous strain was never observed, although increasing the immunizing dose size did frequently reduce oocyst production arising from subsequent heterologous challenge. Differences in cross-protective immunizing capacity between two strains of E. maxima were evident as the H strain consistently stimulated a more potent protective immune response than the W strain. Similarly, increasing the number of immunizing doses of the E. maxima W strain (but not the H strain) increased immune protection against subsequent heterologous challenge. When combined with previously published data the results described here suggest that the E. maxima genome encodes a pool of antigens that are capable of stimulating an immune response cross-protective against more than one strain. These antigens supplement a separate restricted pool of antigens that are capable of stimulating stronger, but strain-specific, protective immune responses.


Insecticide-treated bednets reduce mortality and severe morbidity from malaria among children on the Kenyan coast.
New tools to prevent malaria morbidity and mortality are needed to improve child survival in sub-Saharan Africa. Insecticide treated bednets (ITBN) have been shown, in one setting (The Gambia, West Africa), to reduce childhood mortality. To assess the impact of ITBN on child survival under different epidemiological and cultural conditions we conducted a community randomized, controlled trial of permethrin treated bednets (0.5 g/m2) among a rural population on the Kenyan Coast. Between 1991 and 1993 continuous community-based demographic surveillance linked to hospital-based in-patient surveillance identified all mortality and severe malaria morbidity events during a 2-year period among a population of over 11000 children under 5 years of age. In July 1993, 28 randomly selected communities were issued ITBN, instructed in their use and the nets re-impregnated every 6 months. The remaining 28 communities served as contemporaneous controls for the following 2 years, during which continuous demographic and hospital surveillance was maintained until the end of July 1995. The introduction of ITBN led to significant reductions in childhood mortality (PE 33%, CI 7-51%) and severe, life-threatening malaria among children aged 1-59 months (PE 44%, CI 19-62). These findings confirm the value of ITBN in improving child survival and provide the first evidence of their specific role in reducing severe morbidity from malaria.


Step counts of non-white minority children and youth by gender, grade level, race/ethnicity, and mode of school transportation.
The purposes of this study were to describe and analyze the steps/d of nonwhite minority children and youth by gender, grade level, race/ethnicity, and mode of school transportation. A secondary purpose was to compare the steps/d of minority children and youth to their Caucasian grade-level counterparts. Participants were 547 minority youth grades 5 to 8 from 4 urban schools. Participants wore sealed pedometers for 6 consecutive week/school days. Three hundred and ten participants responded to a questionnaire concerning their mode of transportation to and from school. Statistical analyses indicated a main effect for gender (F(3, 546) = 13.50, P < .001) with no interaction. Boys (12,589 ± 3921) accumulated significantly more steps/d than girls (9,539 ± 3,135). Further analyses also revealed a significant main effect for mode of school transportation (F(2, 309) = 15.97, P ≤ .001). Walkers (12,614 ± 4169) obtained significantly more steps/d than car (10,021 ± 2856) or bus (10,230 ± 3666) transit users. Minority boys obtain similar steps/d as their Caucasian grade-level counterparts; minority girls obtain less steps/d than their Caucasian grade-level counterparts. Minority youth who actively commute are more likely to meet PA recommendations than nonactive commuters.


Characterization of the T-dependent antibody response (TDAR) to keyhole limpet hemocyanin (KLH) in the Göttingen minipig.
Recently, there has been a renewed interest in the use of the minipig as an alternative to dogs and non-human primates for conducting toxicological assessments in non-rodent species. Since the T-dependent antibody response (TDAR) is one of the most widely-accepted assays used in the assessment of immunocompetence, the present study was undertaken to characterize the primary and secondary TDAR to keyhole limpet hemocyanin (KLH) in the Göttingen Minipig(®). Following primary immunization with either 2 or 10 mg KLH, anti-swine IgM and IgG ELISAs were optimized and individual animal responses were evaluated over time. Immunization with 10 mg KLH on Day 0 promoted primary IgM responses that peaked 6-9 days after antigen administration, while primary IgG levels peaked on Day 13 or 14. Secondary IgG antibody levels (following secondary injection with 2 mg KLH on Day 14) plateaued on Days 20-22. Anti-KLH antibody levels were decreased in minipigs treated with cyclophosphamide (CPS), a known immunosuppressant, at doses ranging from 12.5-50 mg/kg/day, while antibody levels in animals treated with 2.5 mg CPS/kg/day were similar to levels in saline-treated swine. These results demonstrate that the Göttingen Minipig(®) can be a useful alternative non-rodent species to the dog and the non-human primate for evaluating the TDAR to KLH in regulatory assessments of immunotoxicity.


Effective Neutrophil Phagocytosis of Aspergillus fumigatus Is Mediated by Classical Pathway Complement Activation.
Aspergillus fumigatus is an important airborne fungal pathogen and a major cause of invasive fungal infections. Susceptible individuals become infected via the inhalation of dormant conidia. If the immune system fails to clear these conidia, they will swell, germinate and grow into large hyphal structures. Neutrophils are essential effector cells for controlling A. fumigatus infection. In general, opsonization of microbial particles is crucial for efficient phagocytosis and killing by neutrophils. Although the antibodies present in human serum do bind to all fungal morphotypes, we observed no direct antibody-mediated phagocytosis of A. fumigatus. We show that opsonization, phagocytosis and killing by neutrophils of A. fumigatus is complement-dependent. Using human sera depleted of key complement components, we investigated the contribution of the different complement initiation pathways in complement activation on the fungal surface. We describe the classical complement pathway as the main initiator of complement activation on A. fumigatus swollen conidia and germ tubes. Antibodies play an important role in complement activation and efficient innate recognition, phagocytosis and killing of A. fumigatus by neutrophils.


DNA damage and cytotoxicity in type II lung epithelial (A549) cell cultures after exposure to diesel exhaust and urban street particles.
Exposure to air pollution particles has been acknowledged to be associated with excess generation of oxidative damage to DNA in experimental model systems and humans. The use of standard reference material (SRM), such as SRM1650 and SRM2975, is advantageous because experiments can be reproduced independently, but exposure to such samples may not mimic the effects observed after exposure to authentic air pollution particles. This study was designed to compare the DNA oxidizing effects of authentic street particles with SRM1650 and SRM2975. The authentic street particles were collected at a traffic intensive road in Copenhagen, Denmark. All of the particles generated strand breaks and oxidized purines in A549 lung epithelial cells in a dose-dependent manner and there were no overt differences in their potency. The exposures also yielded dose-dependent increase of cytotoxicity (as lactate dehydrogenase release) and reduced colony forming ability with slightly stronger cytotoxicity of SRM1650 than of the other particles. In contrast, only the authentic street particles were able to generate 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) in calf thymus DNA, which might be due to the much higher level of transition metals. Authentic street particles and SRMs differ in their ability to oxidize DNA in a cell-free environment, whereas cell culture experiments indicate that the particle preparations elicit a similar alteration of the level of DNA damage and small differences in cytotoxicity. Although it cannot be ruled out that SRMs and authentic street particles might elicit different effects in animal experimental models, this study indicates that on the cellular level, SRM1650 and SRM2975 are suitable surrogate samples for the study of authentic street particles.


Blocking the PI3K/PKB pathway in tumor cells.
A substantial number of experimental and epidemiological studies support an important role for the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB) pathway in the biology of human cancers. Components of this signaling cascade have been found to be deregulated in a wide range of solid tumors and hematologic malignancies, and extensive anti-cancer therapeutic programs are now devoted to the identification of agents that specifically block this molecular pathway. This article focuses on the current knowledge of the alterations of the PI3K/PKB pathway in cancer cells and ongoing drug discovery efforts to therapeutically target it. Particular emphasis is placed on medicinal chemistry activities to identify and develop compounds able to modulate the kinase activity of its main molecular components.


Trends in overweight and obesity over 22 years in a large adult population: the HUNT Study, Norway.
Some reports indicate that the obesity epidemic may be slowing down or halting. We followed body mass index (BMI) and waist circumference (WC) in a large adult population in Norway (n = 90 000) from 1984-1986 (HUNT1) through 1995-1997 (HUNT2) to 2006-2008 (HUNT3) to study whether this is occurring in Norway. Height and weight were measured with standardized and identical methods in all three surveys; WC was also measured in HUNT2 and HUNT3. In the three surveys, mean BMI increased from 25.3 to 26.5 and 27.5 kg m-2 in men and from 25.1 to 26.2 and 26.9 kg m-2 in women. Increase in prevalence of obesity (BMI ≥ 30 kg m-2) was greater in men (from 7.7 to 14.4 and 22.1%) compared with women (from 13.3 to 18.3 and 23.1%). In contrast, women had a greater increase in abdominal obesity (WC ≥ 102 cm for men and WC ≥ 88 cm for women). There was a continuous shift in the distribution curve of BMI and WC to the right, demonstrating that the increase in body weight was occurring in all weight groups, but the increase of obesity was greatest in the youngest age groups. Our data showed no signs of a halt in the increase of obesity in this representative Norwegian population.


Wnt5a is required for cardiac outflow tract septation in mice.
Lack of septation of the cardiac outflow tract (OFT) results in persistent truncus arteriosus (PTA), a form of congenital heart disease. The outflow myocardium expands through addition of cells originating from the pharyngeal mesoderm referred to as secondary/anterior heart field, whereas cardiac neural crest (CNC) cell-derived mesenchyme condenses to form an aortopulmonary septum. We show for the first time that a mutation in Wnt5a in mice leads to PTA. We provide evidence that Wnt5a is expressed in the pharyngeal mesoderm adjacent to CNC cells in both mouse and chicken embryos and in the myocardial cell layer of the conotruncus at the time when CNC cells begin to form the aortopulmonary septum in mice. Although expression domains of secondary heart field markers are not altered in Wnt5a mutant embryos, the expression of CNC cell marker PlexinA2 is significantly reduced. Stimulation of CNC cells with Wnt5a protein elicits Ca2+ transients, suggesting that CNC cells are capable of responding to Wnt5a. We propose a novel model in which Wnt5a produced in the OFT by cells originating from the pharyngeal mesoderm signals to adjacent CNC cells during formation of the aortopulmonary septum through a noncanonical pathway via localized intracellular increases in Ca2+.


Adherence to a Mediterranean diet and risk of fractures in French older persons.
Prevention of fractures is a considerable public health challenge. In a population-based cohort of French elderly people, a diet closer to a Mediterranean type had a borderline significant deleterious effect on the risk of fractures, in part linked to a low consumption of dairy products and a high consumption of fruits. Higher adherence to the Mediterranean diet (MeDi) is linked to a lower risk of several chronic diseases, but its association with the risk of fractures is unclear. Our aim was to investigate the association between MeDi adherence and the risk of fractures in older persons. The sample consisted of 1,482 individuals aged 67 years or older, from Bordeaux, France, included in the Three-City Study in 2001-2002. Occurrences of hip, vertebral and wrist fractures were self-reported every 2 years over 8 years, and 155 incident fractures were recorded. Adherence to the MeDi was evaluated at baseline by a MeDi score, on a 10-point scale based on a food frequency questionnaire and a 24-h recall. Multivariate Cox regression tests were performed to estimate the risk of fractures according to MeDi adherence. Higher MeDi adherence was associated with a non-significant increased risk of fractures at any site (hazard ratio [HR] per 1-point increase of MeDi score = 1.10, P = 0.08) in fully adjusted model. Among MeDi components, higher fruits consumption (>2 servings/day) was significantly associated with an increased risk of hip fractures (HR = 1.95, P = 0.04), while low intake of dairy products was associated with a doubled risk of wrist fractures (HR = 2.03, P = 0.007). An inverse U-shaped association between alcohol intake and risk of total fracture was observed (HR high vs. moderate = 0.61, P for trend = 0.03). Greater MeDi adherence was not associated with a decreased risk of fractures in French older persons. The widely recognized beneficial effects of the MeDi do not seem to apply to bone health in these people.


Chemical Instability and Promiscuity of Arylmethylidenepyrazolinone-Based MDMX Inhibitors.
Targeting the protein-protein interaction between p53 and MDM2/MDMX (MDM4) represents an attractive anticancer strategy for the treatment of p53-competent tumors. Several selective and potent MDM2 inhibitors have been developed and entered the clinic; however, the repertoire of MDMX antagonists is still limited. The arylmethylidenepyrazolinone SJ-172550 has been reported as a selective MDMX antagonist; yet, uncertainties about its mechanism of action have raised doubts about its use as a chemical probe. Here, we show that, in addition to its unclear mode of action, SJ-172550 is unstable in aqueous buffers, giving rise to side products of unknown biological activity. Using an SJ-172550-derived affinity probe, we observed promiscuous binding to cellular proteins whereas cellular thermal shift assays did not reveal a stabilizing effect on MDMX. Overall, our results raise further questions about the interpretation of data using SJ-172550 and related compounds to investigate cellular phenotypes.


Rescuing AAV gene transfer from neutralizing antibodies with an IgG-degrading enzyme.
Preexisting humoral immunity to recombinant adeno-associated virus (AAV) vectors restricts the treatable patient population and efficacy of human gene therapies. Approaches to clear neutralizing antibodies (NAbs), such as plasmapheresis and immunosuppression, are either ineffective or cause undesirable side effects. Here, we describe a clinically relevant strategy to rapidly and transiently degrade NAbs before AAV administration using an IgG-degrading enzyme (IdeZ). We demonstrate that recombinant IdeZ efficiently cleaved IgG in dog, monkey, and human antisera. Prophylactically administered IdeZ cleaved circulating human IgG in mice and prevented AAV neutralization in vivo. In macaques, a single intravenous dose of IdeZ rescued AAV transduction by transiently reversing seropositivity. Importantly, IdeZ efficiently cleaved NAbs and rescued AAV transduction in mice passively immunized with individual human donor sera representing a diverse population. Our antibody clearance approach presents a potentially new paradigm for expanding the prospective patient cohort and improving efficacy of AAV gene therapy.


Modeling range dynamics in heterogeneous landscapes: invasion of the hemlock woolly adelgid in eastern North America.
Range expansion by native and exotic species will continue to be a major component of global change. Anticipating the potential effects of changes in species distributions requires models capable of forecasting population spread across realistic, heterogeneous landscapes and subject to spatiotemporal variability in habitat suitability. Several decades of theory and model development, as well as increased computing power and availability of fine-resolution GIS data, now make such models possible. Still unanswered, however, is the question of how well this new generation of dynamic models will anticipate range expansion. Here we develop a spatially explicit stochastic model that combines dynamic dispersal and population processes with fine-resolution maps characterizing spatiotemporal heterogeneity in climate and habitat to model range expansion of the hemlock woolly adelgid (HWA; Adelges tsugae). We parameterize this model using multiyear data sets describing population and dispersal dynamics of HWA and apply it to eastern North America over a 57-year period (1951-2008). To evaluate the model, the observed pattern of spread of HWA during this same period was compared to model predictions. Our model predicts considerable heterogeneity in the risk of HWA invasion across space and through time, and it suggests that spatiotemporal variation in winter temperature, rather than hemlock abundance, exerts a primary control on the spread of HWA. Although the simulations generally matched the observed current extent of the invasion of HWA and patterns of anisotropic spread, it did not correctly predict when HWA was observed to arrive in different geographic regions. We attribute differences between the modeled and observed dynamics to an inability to capture the timing and direction of long-distance dispersal events that substantially affected the ensuing pattern of spread.


Anticancer Effect of a Novel Proteasome Inhibitor, YSY01A, via G2/M Arrest in PC-3M Cells in vitro and in vivo.
YSY01A is a new tripeptideboronic acid and an analog of PS341. However, YSY01A's antitumor effects and mechanism have not yet been elucidated. This study demonstrates that YSY01A inhibited proteasome activity by combining with the chymotrypsin-like (CT-L) site (β5i/β5), the post-glutamyl peptide hydrolase (PGPH) site (β1i/β1) and the trypsin-like (T-L) site (β2i/β2) in special fluorgonic substrates and proteasome probe tests. We explored the anticancer effect using methyl thiazolyltetrazolium (MTT) or sulforhodamine B (SRB), and PC-3M cells were sensitive to YSY01A among the four cancer cell types tested. The YSY01A antiproliferative effect was stronger than that of PS341. In vivo, YSY01A (1.25, 2.25, and 3.25 mg/kg) inhibited PC-3M cell xenograft tumor growth, and the tumor volume inhibition rate was approximately 40% to 60%. YSY01A arrested PC-3M cells in the G2/M phase of the cell cycle by flow cytometry (FCM). Many proteins related to the cell cycle were analyzed using western blot, and YSY01A was shown to increase p21, p27, cyclinB1, P-cdc2 (tyr15) and wee1 protein expression in both cells and tumor tissue in a concentration-dependent manner. YSY01A, a proteasome inhibitor, exerts anticancer effects on PC-3M cells in vitro and in vivo. The mechanism of the YSY01A-mediated antitumor effect is that the cell cycle is arrested at the G2/M stage. This study suggests that YSY01A may be a novel therapeutic agent for prostate cancer.


Treatment needs and acknowledgement of illness - importance for satisfaction with psychiatric inpatient treatment.
Patient satisfaction is an important, but controversial part of health service evaluation. This study dealt with how acknowledgement of illness and treatment needs effected the distribution of positive, neutral and negative evaluations in a group of first time admitted patients to a psychiatric hospital. The participants filled out a standardized user satisfaction form before discharge. The number of positive, neutral and negative evaluations for each participant was calculated and used as dependent variables in analyses (Classification Tree) where acknowledgement of illness (The Patients' Experience of Hospitalisation Questionnaire) and treatment needs (HoNOS) were used as explanatory variables in addition to a number of potential confounders. Different constellations of variables explained the three dependent variables. The number of positive scores was a function of age and worry (PEH); neutral scores were explained by HoNOS rated social needs and GAF (functional scale), both at admission. Outcome (GAF functional scale) and age explained the number of negative scores. (1) Moderately high negative correlations between positive and neutral scores, and between positive and negative scores, together with a positive correlation between the number of negative and neutral ratings was interpreted to mean that neutral scores sometimes function as undercommunicated negative evaluations. These could better be studied by qualitative methods. (2) The worry subscale (PEH) was important in identifying the majority of patients with the highest numbers of positive scores (patients older than 27.5 yrs with high worry score at admission.). The most dissatisfied group was characterised by denial of both mental problems and need for treatment. (3) Patients with high scores on the HoNOS Social subscale had the highest number of neutral scores. To the extent that neutral evaluations have negative connotations, treatment should focus more effectively on the patients' social needs. (4) The smallest number of negative scores was found among older patients with high functional improvement (GAF F). (5) Increasing age consistently predicted higher satisfaction. A better understanding of why younger patients are more dissatisfied is needed.


Executive summary of the Merck Animal Health Veterinarian Wellbeing Study III and Veterinary Support Staff Study.
Merck Animal Health Veterinarian Wellbeing Study III was conducted to continue to monitor mental health and well being within the veterinary profession in the US and to identify factors associated with high levels of wellbeing and lack of serious psychological distress. A questionnaire consisting of several instruments and questions for measurement of mental health and wellbeing was completed by 2,495 veterinarians and 448 veterinary support staff. Results for veterinarians were weighted to the US AVMA membership. This study revealed that wellbeing and mental health of some veterinarians declined over the past 2 years, driven in part by the COVID-19 pandemic and extreme labor shortages. Burnout remained at a high level, but there was no increase in suicide ideation. A new companion survey of veterinary support staff demonstrated that staff scored lower in wellbeing and mental health, and higher in burnout than veterinarians. Importantly, these studies identified techniques that both individuals and employers may find useful in fostering wellbeing and good mental health. A healthy method for coping with stress and good work-life balance was important, as was engaging a financial adviser for those with student debt or other financial stresses. Employers should create safe environments where employees feel comfortable seeking help, reducing the stigma associated with mental health issues. In addition, employers can provide Employee Assistance Programs and health insurance that covers mental health treatment. Fostering a healthy work culture was also important, one with good communication, teamwork, trust, and adequate time allotted to provide quality patient care.


Independent validation of the prolonged length of stay score.
The prolonged length of stay (PLOS) score has recently been derived and validated in 2 independent national cohorts of acute stroke patients in Israel. The present study aimed to determine the performance of the PLOS score in an independent population-based cohort of stroke patients in a health care system considerably different from that in which the score was derived. The study was performed on all 434 patients with ischemic stroke or intracerebral hemorrhage hospitalized during the first 5 years of the population-based Oxford Vascular Study (OXVASC) in Oxfordshire, UK. Median (interquartile range) length of stay (LOS) and rates of LOS ≥7 days and LOS ≥30 days by the PLOS score were calculated. Model discrimination was assessed by the c-statistic and goodness of fit was evaluated with the Hosmer-Lemeshow test. Median LOS and rates of LOS ≥7 days increased with the increase in PLOS score among all inpatients and hospital survivors. In the analysis of LOS ≥7 days, the PLOS c-statistic (95% CI) was 0.676 (0.618-0.734) for all inpatients and 0.722 (0.664-0.779) for hospital survivors. Findings were similar for LOS ≥30 days. The Hosmer-Lemeshow showed good calibration. The PLOS score successfully predicted PLOS in the OXVASC population of acute stroke patients. Although the score was originally derived for the prediction of prolonged acute hospitalization, it successfully predicted prolonged total LOS.


Strategy of Surgical Resection for Glioma Based on Intraoperative Functional Mapping and Monitoring.
A growing number of papers have pointed out the relationship between aggressive resection of gliomas and survival prognosis. For maximum resection, the current concept of surgical decision-making is in "information-guided surgery" using multimodal intraoperative information. With this, anatomical information from intraoperative magnetic resonance imaging (MRI) and navigation, functional information from brain mapping and monitoring, and histopathological information must all be taken into account in the new perspective for innovative minimally invasive surgical treatment of glioma. Intraoperative neurofunctional information such as neurophysiological functional monitoring takes the most important part in the process to acquire objective visual data during tumor removal and to integrate these findings as digitized data for intraoperative surgical decision-making. Moreover, the analysis of qualitative data and threshold-setting for quantitative data raise difficult issues in the interpretation and processing of each data type, such as determination of motor evoked potential (MEP) decline, underestimation in tractography, and judgments of patient response for neurofunctional mapping and monitoring during awake craniotomy. Neurofunctional diagnosis of false-positives in these situations may affect the extent of resection, while false-negatives influence intra- and postoperative complication rates. Additionally, even though the various intraoperative visualized data from multiple sources contribute significantly to the reliability of surgical decisions when the information is integrated and provided, it is not uncommon for individual pieces of information to convey opposing suggestions. Such conflicting pieces of information facilitate higher-order decision-making that is dependent on the policies of the facility and the priorities of the patient, as well as the availability of the histopathological characteristics from resected tissue.


Intervention to reduce transmission of resistant bacteria in intensive care.
Intensive care units (ICUs) are high-risk settings for the transmission of methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococcus (VRE). In a cluster-randomized trial, we evaluated the effect of surveillance for MRSA and VRE colonization and of the expanded use of barrier precautions (intervention) as compared with existing practice (control) on the incidence of MRSA or VRE colonization or infection in adult ICUs. Surveillance cultures were obtained from patients in all participating ICUs; the results were reported only to ICUs assigned to the intervention. In intervention ICUs, patients who were colonized or infected with MRSA or VRE were assigned to care with contact precautions; all the other patients were assigned to care with universal gloving until their discharge or until surveillance cultures obtained at admission were reported to be negative. During a 6-month intervention period, there were 5434 admissions to 10 intervention ICUs, and 3705 admissions to 8 control ICUs. Patients who were colonized or infected with MRSA or VRE were assigned to barrier precautions more frequently in intervention ICUs than in control ICUs (a median of 92% of ICU days with either contact precautions or universal gloving [51% with contact precautions and 43% with universal gloving] in intervention ICUs vs. a median of 38% of ICU days with contact precautions in control ICUs, P<0.001). In intervention ICUs, health care providers used clean gloves, gowns, and hand hygiene less frequently than required for contacts with patients assigned to barrier precautions; when contact precautions were specified, gloves were used for a median of 82% of contacts, gowns for 77% of contacts, and hand hygiene after 69% of contacts, and when universal gloving was specified, gloves were used for a median of 72% of contacts and hand hygiene after 62% of contacts. The mean (±SE) ICU-level incidence of events of colonization or infection with MRSA or VRE per 1000 patient-days at risk, adjusted for baseline incidence, did not differ significantly between the intervention and control ICUs (40.4±3.3 and 35.6±3.7 in the two groups, respectively; P=0.35). The intervention was not effective in reducing the transmission of MRSA or VRE, although the use of barrier precautions by providers was less than what was required. (Funded by the National Institute of Allergy and Infectious Diseases and others; STAR*ICU ClinicalTrials.gov number, NCT00100386.).


Frontal alpha oscillations distinguish leaders from followers: multivariate decoding of mutually interacting brains.
Successful social interactions rely upon the abilities of two or more people to mutually exchange information in real-time, while simultaneously adapting to one another. The neural basis of social cognition has mostly been investigated in isolated individuals, and more recently using two-person paradigms to quantify the neuronal dynamics underlying social interaction. While several studies have shown the relevance of understanding complementary and mutually adaptive processes, the neural mechanisms underlying such coordinative behavioral patterns during joint action remain largely unknown. Here, we employed a synchronized finger-tapping task while measuring dual-EEG from pairs of human participants who either mutually adjusted to each other in an interactive task or followed a computer metronome. Neurophysiologically, the interactive condition was characterized by a stronger suppression of alpha and low-beta oscillations over motor and frontal areas in contrast to the non-interactive computer condition. A multivariate analysis of two-brain activity to classify interactive versus non-interactive trials revealed asymmetric patterns of the frontal alpha-suppression in each pair, during both task anticipation and execution, such that only one member showed the frontal component. Analysis of the behavioral data showed that this distinction coincided with the leader-follower relationship in 8/9 pairs, with the leaders characterized by the stronger frontal alpha-suppression. This suggests that leaders invest more resources in prospective planning and control. Hence our results show that the spontaneous emergence of leader-follower relationships in dyadic interactions can be predicted from EEG recordings of brain activity prior to and during interaction. Furthermore, this emphasizes the importance of investigating complementarity in joint action.


Prediction of significant prostate cancer in biopsy-naïve men: Validation of a novel risk model combining MRI and clinical parameters and comparison to an ERSPC risk calculator and PI-RADS.
Risk models (RM) need external validation to assess their value beyond the setting in which they were developed. We validated a RM combining mpMRI and clinical parameters for the probability of harboring significant prostate cancer (sPC, Gleason Score ≥ 3+4) for biopsy-naïve men. The original RM was based on data of 670 biopsy-naïve men from Heidelberg University Hospital who underwent mpMRI with PI-RADS scoring prior to MRI/TRUS-fusion biopsy 2012-2015. Validity was tested by a consecutive cohort of biopsy-naïve men from Heidelberg (n = 160) and externally by a cohort of 133 men from University College London Hospital (UCLH). Assessment of validity was performed at fusion-biopsy by calibration plots, receiver operating characteristics curve and decision curve analyses. The RM`s performance was compared to ERSPC-RC3, ERSPC-RC3+PI-RADSv1.0 and PI-RADSv1.0 alone. SPC was detected in 76 men (48%) at Heidelberg and 38 men (29%) at UCLH. The areas under the curve (AUC) were 0.86 for the RM in both cohorts. For ERSPC-RC3+PI-RADSv1.0 the AUC was 0.84 in Heidelberg and 0.82 at UCLH, for ERSPC-RC3 0.76 at Heidelberg and 0.77 at UCLH and for PI-RADSv1.0 0.79 in Heidelberg and 0.82 at UCLH. Calibration curves suggest that prevalence of sPC needs to be adjusted to local circumstances, as the RM overestimated the risk of harboring sPC in the UCLH cohort. After prevalence-adjustment with respect to the prevalence underlying ERSPC-RC3 to ensure a generalizable comparison, not only between the Heidelberg and die UCLH subgroup, the RM`s Net benefit was superior over the ERSPC`s and the mpMRI`s for threshold probabilities above 0.1 in both cohorts. The RM discriminated well between men with and without sPC at initial MRI-targeted biopsy but overestimated the sPC-risk at UCLH. Taking prevalence into account, the model demonstrated benefit compared with clinical risk calculators and PI-RADSv1.0 in making the decision to biopsy men at suspicion of PC. However, prevalence differences must be taken into account when using or validating the presented risk model.


Ionized alkaline water: new strategy for management of metabolic acidosis in experimental animals.
Metabolic acidosis can occur as a result of either the accumulation of endogenous acids or loss of bicarbonate from the gastrointestinal tract or the kidney, which represent common causes of metabolic acidosis. The appropriate treatment of acute metabolic acidosis has been very controversial. Ionized alkaline water was not evaluated in such groups of patients in spite of its safety and reported benefits. So, we aimed to assess its efficacy in the management of metabolic acidosis in animal models. Two models of metabolic acidosis were created in dogs and rats. The first model of renal failure was induced by ligation of both ureters; and the second model was induced by urinary diversion to gut (gastrointestinal bicarbonate loss model). Both models were subjected to ionized alkaline water (orally and by hemodialysis). Dogs with renal failure were assigned to two groups according to the type of dialysate utilized during hemodialysis sessions, the first was utilizing alkaline water and the second was utilizing conventional water. Another two groups of animals with urinary diversion were arranged to receive oral alkaline water and tap water. In renal failure animal models, acid-base parameters improved significantly after hemodialysis with ionized alkaline water compared with the conventional water treated with reverse osmosis (RO). Similar results were observed in urinary diversion models as there was significant improvement of both the partial pressure of carbon dioxide and serum bicarbonate (P = 0.007 and 0.001 respectively) after utilizing alkaline water orally. Alkaline ionized water can be considered as a major safe strategy in the management of metabolic acidosis secondary to renal failure or dialysis or urinary diversion. Human studies are indicated in the near future to confirm this issue in humans.


Localization of polysome-bound albumin and serine dehydratase in rat liver cell fractions.
The polysomes involved in albumin and serine dehydratase synthesis were identified and localized by the binding to rat liver polysomes of anti-rat serum albumin and anti-serine dehydratase [(125)I]Fab dimer and monomer. Techniques were developed for the isolation of undegraded free and membrane-bound polysomes and for the preparation of [(125)I]Fab monomers and dimers from the IgG obtained from the antisera to the two proteins, rat serum albumin and serine dehydratase. The distribution of anti-rat serum albumin [(125)I]Fab dimer in the polysome profile is in accordance with the size of polysomes that are expected to be synthesizing albumin. By direct precipitation, it has been demonstrated that nascent chains isolated from the membrane-bound polysomes by puromycin were precipitated by anti-rat serum albumin-IgG at a level of 5-6 times those released from free polysomes. Anti-rat serum albumin-[(125)I]Fab dimer reacted with membrane-bound polysomes almost exclusively compared to the binding of nonimmune, control [(125)I]Fab dimer; a significant degree of binding of anti-rat serum albumin-[(125)I]Fab to free polysomes was also obtained. The [(125)I]Fab dimer made from normal control rabbit serum does not react with polysomes from liver at all and this preparation will not interact with polysomes extracted from tissues that do not synthesize rat serum albumin. Both anti-serine dehydratase-[(125)I]Fab monomer and dimer react with free and bound polysomes from livers of animals fed a chow diet or those fed a high 90% protein diet and given glucagon. In the latter instance, however, it is clear that the majority of the binding occurs to the bound polysomes. Furthermore, the specificity of this reaction may be further shown by the use of kidney polysomes that do not normally synthesize serine dehydratase. When these latter polysomes are isolated, even after the addition of crude and purified serine dehydratase, no reaction with anti-serine dehydratase-Fab fragments could be demonstrated. These results indicate that the reaction of the Fab fragments are specific for polysomes that synthesize rat serum albumin or rat liver serine dehydratase. Furthermore, they demonstrate that even with this high degree of specificity, some polysomes in the fraction labeled "free" are in the process of synthesizing rat serum albumin while bound polysomes to a significant, if not major, degree are the site of the synthesis of rat liver serine dehydratase.


Non-invasive assessment of disease progression and neuroprotective effects of dietary coconut oil supplementation in the ALS SOD1G93A mouse model: A 1H-magnetic resonance spectroscopic study.
Amyotrophic Lateral Sclerosis (ALS) is an incurable neurodegenerative disease primarily characterized by progressive degeneration of motor neurons in the motor cortex, brainstem and spinal cord. Due to relatively fast progression of ALS, early diagnosis is essential for possible therapeutic intervention and disease management. To identify potential diagnostic markers, we investigated age-dependent effects of disease onset and progression on regional neurochemistry in the SOD1G93A ALS mouse model using localized in vivo magnetic resonance spectroscopy (MRS). We focused mainly on the brainstem region since brainstem motor nuclei are the primarily affected regions in SOD1G93A mice and ALS patients. In addition, metabolite profiles of the motor cortex were also assessed. In the brainstem, a gradual decrease in creatine levels were detected starting from the pre-symptomatic age of 70 days postpartum. During the early symptomatic phase (day 90), a significant increase in the levels of the inhibitory neurotransmitter γ- aminobutyric acid (GABA) was measured. At later time points, alterations in the form of decreased NAA, glutamate, glutamine and increased myo-inositol were observed. Also, decreased glutamate, NAA and increased taurine levels were seen at late stages in the motor cortex. A proof-of-concept (PoC) study was conducted to assess the effects of coconut oil supplementation in SODG93A mice. The PoC revealed that the coconut oil supplementation together with the regular diet delayed disease symptoms, enhanced motor performance, and prolonged survival in the SOD1G93A mouse model. Furthermore, MRS data showed stable metabolic profile at day 120 in the coconut oil diet group compared to the group receiving a standard diet without coconut oil supplementation. In addition, a positive correlation between survival and the neuronal marker NAA was found. To the best of our knowledge, this is the first study that reports metabolic changes in the brainstem using in vivo MRS and effects of coconut oil supplementation as a prophylactic treatment in SOD1G93A mice.


A new biomarker to examine the role of hippocampal function in the development of spatial reorientation in children: a review.
Spatial navigation is an adaptive skill that involves determining the route to a particular goal or location, and then traveling that path. A major component of spatial navigation is spatial reorientation, or the ability to reestablish a sense of direction after being disoriented. The hippocampus is known to be critical for navigating, and has more recently been implicated in reorienting in adults, but relatively little is known about the development of the hippocampus in relation to these large-scale spatial abilities in children. It has been established that, compared to school-aged children, preschool children tend to perform poorly on certain spatial reorientation tasks, suggesting that their hippocampi may not be mature enough to process the demands of such a task. Currently, common techniques used to examine underlying brain activity, such as electroencephalography (EEG) and functional magnetic resonance imaging (fMRI), are not suitable for examining hippocampal development in young children. In the present paper, we argue instead for the use of eyeblink conditioning (EBC), a relatively under-utilized, inexpensive, and safe method that is easy to implement in developing populations. In addition, EBC has a well defined neural circuitry, which includes the hippocampus, making it an ideal tool to indirectly measure hippocampal functioning in young children. In this review, we will evaluate the literature on EBC and its relation to hippocampal development, and discuss the possibility of using EBC as an objective measure of associative learning in relation to large-scale spatial skills. We support the use of EBC as a way to indirectly access hippocampal function in typical and atypical populations in order to characterize the neural substrates associated with the development of spatial reorientation abilities in early childhood. As such, EBC is a potential, simple biomarker for success in tasks that require the hippocampus, including spatial reorientation.


Lineage hierarchies and stochasticity ensure the long-term maintenance of adult neural stem cells.
The cellular basis and extent of neural stem cell (NSC) self-renewal in adult vertebrates, and their heterogeneity, remain controversial. To explore the functional behavior and dynamics of individual NSCs, we combined genetic lineage tracing, quantitative clonal analysis, intravital imaging, and global population assessments in the adult zebrafish telencephalon. Our results are compatible with a model where adult neurogenesis is organized in a hierarchy in which a subpopulation of deeply quiescent reservoir NSCs with long-term self-renewal potential generate, through asymmetric divisions, a pool of operational NSCs activating more frequently and taking stochastic fates biased toward neuronal differentiation. Our data further suggest the existence of an additional, upstream, progenitor population that supports the continuous generation of new reservoir NSCs, thus contributing to their overall expansion. Hence, we propose that the dynamics of vertebrate neurogenesis relies on a hierarchical organization where growth, self-renewal, and neurogenic functions are segregated between different NSC types.


Hemodynamic deterioration in chronic venous disease.
Clinical deterioration of patients with chronic venous disease (CVD) has been well described and a standardized classification has been proposed. The progressive hemodynamic deterioration producing these clinical findings is less well appreciated. This study examines and correlates venous hemodynamics with clinical severity in patients with CVD. Two hundred seventy-four extremities from 149 patients with varying degrees of CVD and 56 extremities from 28 symptom-free volunteers were evaluated clinically and hemodynamically. Each limb was assessed for functional venous volume, degree of valvular insufficiency, efficiency of the calf muscle pump, and noninvasive estimate of ambulatory venous pressure. In addition, exercise venous pressures were recorded in 56 extremities from 36 patients and 9 extremities from 6 volunteers. As CVD progresses from class 0 to class 2, venous volume expands, valvular function deteriorates, the calf muscle pump becomes inefficient, and ambulatory venous hypertension develops. However, once extremities develop brawny edema or hyperpigmentation, further deterioration of limb hemodynamics does not occur. Patients with deep venous obstruction have more severe valvular insufficiency, calf muscle pump dysfunction, and ambulatory venous hypertension than have patients without evidence of obstruction. Residual volume fraction offers a reliable noninvasive estimate of ambulatory venous pressure (r = 0.76), although its correlation was significantly better for patients without venous obstruction (r = 0.86) than for those with obstruction (r = 0.40; p < 0.05). Deterioration in venous hemodynamics parallels clinical severity through class 2. Once brawny edema and hyperpigmentation occur, ulceration develops without additional deterioration of venous hemodynamics.


Transport properties of melanosomes along microtubules interpreted by a tug-of-war model with loose mechanical coupling.
In this work, we explored theoretically the transport of organelles driven along microtubules by molecular motors of opposed polarities using a stochastic model that considers a Langevin dynamics for the cargo, independent cargo-motor linkers and stepping motion for the motors. It has been recently proposed that the stiffness of the motor plays an important role when multiple motors collectively transport a cargo. Therefore, we considered in our model the recently reported values for the stiffness of the cargo-motor linker determined in living cells (∼0.01 pN/nm,) which is significantly lower than the motor stiffness obtained in in vitro assays and used in previous studies. Our model could reproduce the multimodal velocity distributions and typical trajectory characteristics including the properties of the reversions in the overall direction of motion observed during melanosome transport along microtubules in Xenopus laevis melanophores. Moreover, we explored the contribution of the different motility states of the cargo-motor system to the different modes of the velocity distributions and could identify the microscopic mechanisms of transport leading to trajectories compatible with those observed in living cells. Finally, by changing the attachment and detachment rates, the model could reproduce the different velocity distributions observed during melanosome transport along microtubules in Xenopus laevis melanophores stimulated for aggregation and dispersion. Our analysis suggests that active tug-of-war processes with loose mechanical coupling can account for several aspects of cargo transport along microtubules in living cells.